Synovial fibroblasts promote immunoglobulin class switching by a mechanism involving BAFF

Eur J Immunol. 2011 Jul;41(7):2113-22. doi: 10.1002/eji.201041194. Epub 2011 May 20.

Abstract

Fibroblast-like synoviocytes (FLSs) are important actors in rheumatoid arthritis (RA) pathogenesis. The autoimmune nature of RA is attributed to autoantibody production, which confers to B cells a predominant role in RA. Several arguments support an induction of class switch recombination (CSR) in RA synovium, causing--in conjunction with somatic hypermutation--the production of potentially pathogenic IgG. To determine whether RA FLSs can directly promote CSR and to analyze the role of external factors like TLR signals and BAFF (B cell activating factor) family cytokines in this FLS-B cell crosstalk, we performed cocultures of blood B cells (from normal individuals or RA patients) with RA FLSs and analyzed CSR induction by quantification of AICDA (encoding activation-induced cytidine deaminase, AID) and switch circular transcripts expression, and IgG secretion. RA FLSs--and to a lesser extent osteoarthritis or control FLSs--promoted CSR, and TLR3 stimulation potentialized it. In addition, induction of CSR by RA FLSs was totally dependent on cell-cell contact in basal conditions, and partially dependent in the case of TLR3 stimulation. Finally, we showed that the mechanism by which RA FLSs induce CSR is mostly BAFF-dependent. Our results support the hypothesis that CSR can be induced outside the ectopic lymphoid structures in RA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arthritis, Rheumatoid / immunology*
  • Arthritis, Rheumatoid / pathology
  • Autoantibodies / biosynthesis
  • B-Cell Activating Factor / metabolism*
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Cells, Cultured
  • Coculture Techniques
  • Cytidine Deaminase / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Fibroblasts / metabolism
  • Humans
  • Immunoglobulin Class Switching*
  • Immunoglobulin G / biosynthesis*
  • Immunoglobulin G / metabolism
  • Immunoglobulin Switch Region
  • Osteoarthritis / immunology
  • Osteoarthritis / pathology
  • Polymerase Chain Reaction
  • Somatic Hypermutation, Immunoglobulin
  • Synovial Membrane / cytology*
  • Synovial Membrane / metabolism
  • Toll-Like Receptor 3 / metabolism

Substances

  • Autoantibodies
  • B-Cell Activating Factor
  • Immunoglobulin G
  • TNFSF13B protein, human
  • Toll-Like Receptor 3
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase